US20200071382A1 - Tgf-beta superfamily heteromultimers and uses thereof - Google Patents

Tgf-beta superfamily heteromultimers and uses thereof Download PDF

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US20200071382A1
US20200071382A1 US16/315,338 US201716315338A US2020071382A1 US 20200071382 A1 US20200071382 A1 US 20200071382A1 US 201716315338 A US201716315338 A US 201716315338A US 2020071382 A1 US2020071382 A1 US 2020071382A1
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polypeptide
seq
amino acids
heteromultimer
tgf
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Ravindra Kumar
Asya Grinberg
Dianne Sako
Roselyne Castonguay
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Acceleron Pharma Inc
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Acceleron Pharma Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P7/06—Antianaemics
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    • C07—ORGANIC CHEMISTRY
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    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70596—Molecules with a "CD"-designation not provided for elsewhere
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C12N15/8509—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic
    • C12N2015/8518—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells for producing genetically modified animals, e.g. transgenic expressing industrially exogenous proteins, e.g. for pharmaceutical use, human insulin, blood factors, immunoglobulins, pseudoparticles

Definitions

  • TGF-beta The transforming growth factor-beta (TGF-beta) superfamily contains a variety of growth factors that share common sequence elements and structural motifs. These proteins are known to exert biological effects on a large variety of cell types in both vertebrates and invertebrates. Members of the superfamily perform important functions during embryonic development in pattern formation and tissue specification and can influence a variety of differentiation processes, including adipogenesis, myogenesis, chondrogenesis, cardiogenesis, hematopoiesis, neurogenesis, and epithelial cell differentiation.
  • TGF-beta family members have diverse, often complementary biological effects. By manipulating the activity of a member of the TGF-beta family, it is often possible to cause significant physiological changes in an organism. For example, the Piedmontese and Belgian Blue cattle breeds carry a loss-of-function mutation in the GDF8 (also called myostatin) gene that causes a marked increase in muscle mass.
  • GDF8 also called myostatin
  • Changes in bone, red blood cells, and other tissues may be achieved by enhancing or inhibiting signaling (e.g., SMAD 1, 2, 3, 5, and/or 8) that is mediated by ligands of the TGF-beta family.
  • signaling e.g., SMAD 1, 2, 3, 5, and/or 8
  • the disclosure provides recombinant TGF-beta superfamily heteromultimers (heteromultimers) comprising at least one TGF-beta superfamily co-receptor polypeptide (e.g., endoglin, betaglycan, Cripto-1, Cryptic, Cryptic family protein 1B, Crim1, Crim2, BAMBI, BMPER, RGM-A, RGM-B, MuSK, and hemojuvelin), including fragments and variants thereof.
  • TGF-beta superfamily co-receptor polypeptide e.g., endoglin, betaglycan, Cripto-1, Cryptic, Cryptic family protein 1B, Crim1, Crim2, BAMBI, BMPER, RGM-A, RGM-B, MuSK, and hemojuvelin
  • the disclosure relates to a recombinant heteromultimer comprising a TGF-beta superfamily co-receptor polypeptide selected from the group consisting of: endoglin, betaglycan, Cripto-1, Cryptic, Cryptic family protein 1B, Crim1, Crim2, BAMBI, BMPER, RGM-A, RGM-B, MuSK, and hemojuvelin, including fragments and variants thereof, and a TGF-beta superfamily type I receptor polypeptide selected from the group consisting of: ALK1, ALK2, ALK3, ALK4, ALK5, ALK6, and ALK7, including fragments and variants thereof.
  • a TGF-beta superfamily co-receptor polypeptide selected from the group consisting of: endoglin, betaglycan, Cripto-1, Cryptic, Cryptic family protein 1B, Crim1, Crim2, BAMBI, BMPER, RGM-A, RGM-B, MuSK, and
  • the disclosure relates to a recombinant heteromultimer comprising a TGF-beta superfamily co-receptor polypeptide selected from the group consisting of: endoglin, betaglycan, Cripto-1, Cryptic, Cryptic family protein 1B, Crim1, Crim2, BAMBI, BMPER, RGM-A, RGM-B, MuSK, and hemojuvelin, including fragments and variants thereof, and a TGF-beta superfamily type II receptor polypeptide selected from the group consisting of: ActRIIA, ActRIIB, TGFBRII, BMPRII, and MISRII, including fragments and variants thereof.
  • a TGF-beta superfamily co-receptor polypeptide selected from the group consisting of: endoglin, betaglycan, Cripto-1, Cryptic, Cryptic family protein 1B, Crim1, Crim2, BAMBI, BMPER, RGM-A, RGM-B,
  • the disclosure relates to a recombinant heteromultimer comprising a first TGF-beta superfamily co-receptor polypeptide selected from the group consisting of: endoglin, betaglycan, Cripto-1, Cryptic, Cryptic family protein 1B, Crim1, Crim2, BAMBI, BMPER, RGM-A, RGM-B, MuSK, and hemojuvelin, including fragments and variants thereof, and a second TGF-beta superfamily co-receptor polypeptide selected from the group consisting of: endoglin, betaglycan, Cripto-1, Cryptic, Cryptic family protein 1B, Crim1, Crim2, BAMBI, BMPER, RGM-A, RGM-B, MuSK, and hemojuvelin, including fragments and variants thereof.
  • a first TGF-beta superfamily co-receptor polypeptide selected from the group consisting of: endoglin, betaglycan, Cripto
  • TGF-beta superfamily co-receptor, type I receptor, and type II receptor polypeptides as described herein comprise a ligand-binding domain of the receptor, for example, an extracellular domain of a TGF-beta superfamily co-receptor, type I receptor, or type II receptor.
  • polypeptides and heteromultimers of the disclosure e.g., co-receptor:type I receptor, co-receptor:type II receptor, and co-receptor:co-receptor heteromultimers
  • heteromultimers of the disclosure bind to one or more TGF-beta superfamily ligands (e.g., BMP2, BMP2/7, BMP3, BMP4, BMP4/7, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP9, BMP10, GDF3, GDF5, GDF6/BMP13, GDF7, GDF8, GDF9b/BMP15, GDF11/BMP11, GDF15/MIC1, TGF- ⁇ 1, TGF- ⁇ 2, TGF- ⁇ 3, activin A, activin B, activin C, activin E, activin AB, activin AC, activin AE, activin BC, activin BE, nodal, glial cell-derived neurotrophic factor (GDNF), neurturin, artemin, persephin,
  • TGF-beta superfamily ligands e.g., BMP2, BMP2/7, BMP3, BMP4, BMP4/7, BMP5, BMP6, BMP
  • a heteromultimer e.g., co-receptor:type I receptor, co-receptor:type II receptor, and co-receptor:co-receptor heteromultimers
  • a heteromultimer of the disclosure e.g., co-receptor:type I receptor, co-receptor:type II receptor, and co-receptor:co-receptor heteromultimers
  • has a different TGF-beta superfamily ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer e.g., endoglin:ALK1 heteromultimer vs. endoglin and ALK1 homomultimers.
  • a heteromultimer of the disclosure may inhibit one or more TGF-beta superfamily ligands (e.g., BMP2, BMP2/7, BMP3, BMP4, BMP4/7, BMP5, BMP6, BMP7, BMP8a, BMP8b, BMP9, BMP10, GDF3, GDF5, GDF6/BMP13, GDF7, GDF8, GDF9b/BMP15, GDF11/BMP11, GDF15/MIC1, TGF- ⁇ 1, TGF- ⁇ 2, TGF- ⁇ 3, activin A, activin B, activin C, activin E, activin AB, activin AC, activin AE, activin BC, activin BE, nodal, glial cell-derived neurotrophic factor (GDNF), neurturin, artemin, persephin,
  • TGF-beta superfamily ligands e.g., BMP2, BMP2/7, BMP3, BMP4, BMP4/7, BMP5, BMP6, B
  • a heteromultimer of the disclosure may inhibit signaling of one or more TGF-beta superfamily ligands.
  • a heteromultimer of the disclosure e.g., co-receptor:type I receptor, co-receptor:type II receptor, and co-receptor:co-receptor heteromultimers
  • heteromultimers of the disclosure are heterodimers.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • the endoglin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the endoglin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • endoglin:ALK1 heteromultimers are soluble.
  • an endoglin:ALK1 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an endoglin:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an endoglin:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and ALK1 homomultimers).
  • a corresponding homomultimer e.g., endoglin and ALK1 homomultimers.
  • an endoglin:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • the endoglin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the endoglin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • endoglin:ALK2 heteromultimers are soluble.
  • an endoglin:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an endoglin:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an endoglin:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and ALK2 homomultimers).
  • a corresponding homomultimer e.g., endoglin and ALK2 homomultimers.
  • an endoglin:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • the endoglin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the endoglin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • endoglin:ALK3 heteromultimers are soluble.
  • an endoglin:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an endoglin:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an endoglin:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and ALK3 homomultimers).
  • a corresponding homomultimer e.g., endoglin and ALK3 homomultimers.
  • an endoglin:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • the endoglin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the endoglin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the endoglin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • endoglin:ALK4 heteromultimers are soluble.
  • an endoglin:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an endoglin:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an endoglin:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and ALK4 homomultimers).
  • a corresponding homomultimer e.g., endoglin and ALK4 homomultimers.
  • an endoglin:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • the endoglin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the endoglin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the endoglin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • endoglin:ALK5 heteromultimers are soluble.
  • an endoglin:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an endoglin:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an endoglin:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and ALK5 homomultimers).
  • a corresponding homomultimer e.g., endoglin and ALK5 homomultimers.
  • an endoglin:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • the endoglin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the endoglin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the endoglin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • endoglin:ALK6 heteromultimers are soluble.
  • an endoglin:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an endoglin:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an endoglin:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and ALK6 homomultimers).
  • a corresponding homomultimer e.g., endoglin and ALK6 homomultimers.
  • an endoglin:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • the endoglin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the endoglin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the endoglin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the endoglin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the endoglin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • endoglin:ALK7 heteromultimers are soluble.
  • an endoglin:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an endoglin:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an endoglin:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and ALK7 homomultimers).
  • a corresponding homomultimer e.g., endoglin and ALK7 homomultimers.
  • an endoglin:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • the betaglycan:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the betaglycan:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • betaglycan:ALK1 heteromultimers are soluble.
  • an betaglycan:ALK1 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an betaglycan:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an betaglycan:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and ALK1 homomultimers).
  • a corresponding homomultimer e.g., betaglycan and ALK1 homomultimers.
  • an betaglycan:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • the betaglycan:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the betaglycan:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • betaglycan:ALK2 heteromultimers are soluble.
  • an betaglycan:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an betaglycan:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an betaglycan:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and ALK2 homomultimers).
  • a corresponding homomultimer e.g., betaglycan and ALK2 homomultimers.
  • an betaglycan:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • the betaglycan:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the betaglycan:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • betaglycan:ALK3 heteromultimers are soluble.
  • an betaglycan:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an betaglycan:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an betaglycan:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and ALK3 homomultimers).
  • a corresponding homomultimer e.g., betaglycan and ALK3 homomultimers.
  • an betaglycan:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • the betaglycan:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the betaglycan:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the betaglycan:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • betaglycan:ALK4 heteromultimers are soluble.
  • an betaglycan:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an betaglycan:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an betaglycan:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and ALK4 homomultimers).
  • a corresponding homomultimer e.g., betaglycan and ALK4 homomultimers.
  • an betaglycan:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • the betaglycan:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the betaglycan:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the betaglycan:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • betaglycan:ALK5 heteromultimers are soluble.
  • an betaglycan:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an betaglycan:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an betaglycan:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and ALK5 homomultimers).
  • a corresponding homomultimer e.g., betaglycan and ALK5 homomultimers.
  • an betaglycan:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • the betaglycan:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the betaglycan:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the betaglycan:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • betaglycan:ALK6 heteromultimers are soluble.
  • an betaglycan:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an betaglycan:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an betaglycan:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and ALK6 homomultimers).
  • a corresponding homomultimer e.g., betaglycan and ALK6 homomultimers.
  • an betaglycan:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • the betaglycan:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the betaglycan:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the betaglycan:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the betaglycan:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the betaglycan:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • betaglycan:ALK7 heteromultimers are soluble.
  • an betaglycan:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an betaglycan:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an betaglycan:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and ALK7 homomultimers).
  • a corresponding homomultimer e.g., betaglycan and ALK7 homomultimers.
  • an betaglycan:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • the Cripto-1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the Cripto-1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • Cripto-1:ALK1 heteromultimers are soluble.
  • an Cripto-1:ALK1 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an Cripto-1:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an Cripto-1:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and ALK1 homomultimers).
  • a corresponding homomultimer e.g., Cripto-1 and ALK1 homomultimers.
  • an Cripto-1:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • the Cripto-1:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the Cripto-1:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • Cripto-1:ALK2 heteromultimers are soluble.
  • an Cripto-1:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an Cripto-1:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an Cripto-1:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and ALK2 homomultimers).
  • a corresponding homomultimer e.g., Cripto-1 and ALK2 homomultimers.
  • an Cripto-1:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • the Cripto-1:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the Cripto-1:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • Cripto-1:ALK3 heteromultimers are soluble.
  • an Cripto-1:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • an Cripto-1:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • an Cripto-1:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and ALK3 homomultimers).
  • a corresponding homomultimer e.g., Cripto-1 and ALK3 homomultimers.
  • an Cripto-1:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • the Cripto-1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the Cripto-1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the Cripto-1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • Cripto-1:ALK4 heteromultimers are soluble.
  • a Cripto-1:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cripto-1:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cripto-1:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and ALK4 homomultimers).
  • a Cripto-1:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • the Cripto-1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the Cripto-1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the Cripto-1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • Cripto-1:ALK5 heteromultimers are soluble.
  • a Cripto-1:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cripto-1:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cripto-1:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and ALK5 homomultimers).
  • a Cripto-1:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • the Cripto-1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the Cripto-1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the Cripto-1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • Cripto-1:ALK6 heteromultimers are soluble.
  • a Cripto-1:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cripto-1:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cripto-1:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and 6 homomultimers).
  • a Cripto-1:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • the Cripto-1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the Cripto-1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the Cripto-1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the Cripto-1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the Cripto-1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • Cripto-1:ALK7 heteromultimers are soluble.
  • a Cripto-1:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cripto-1:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cripto-1:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and ALK7 homomultimers).
  • a Cripto-1:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • the Cryptic protein:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the Cryptic protein:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • Cryptic protein:ALK1 heteromultimers are soluble.
  • a Cryptic protein:ALK1 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and ALK1 homomultimers).
  • a Cryptic protein:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • the Cryptic protein:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the Cryptic protein:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • Cryptic protein:ALK2 heteromultimers are soluble.
  • a Cryptic protein:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and ALK2 homomultimers).
  • a Cryptic protein:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • the Cryptic protein:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the Cryptic protein:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • Cryptic protein:ALK3 heteromultimers are soluble.
  • a Cryptic protein:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and ALK3 homomultimers).
  • a Cryptic protein:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • the Cryptic protein:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the Cryptic protein:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the Cryptic protein:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • Cryptic protein:ALK4 heteromultimers are soluble.
  • a Cryptic protein:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and ALK4 homomultimers).
  • a Cryptic protein:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • the Cryptic protein:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the Cryptic protein:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the Cryptic protein:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • Cryptic protein:ALK5 heteromultimers are soluble.
  • a Cryptic protein:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and ALK5 homomultimers).
  • a Cryptic protein:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • the Cryptic protein:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the Cryptic protein:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the Cryptic protein:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • Cryptic protein:ALK6 heteromultimers are soluble.
  • a Cryptic protein:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and ALK6 homomultimers).
  • a Cryptic protein:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • the Cryptic protein:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the Cryptic protein:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the Cryptic protein:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the Cryptic protein:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the Cryptic protein:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • Cryptic protein:ALK7 heteromultimers are soluble.
  • a Cryptic protein:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and ALK7 homomultimers).
  • a Cryptic protein:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • the Cryptic family protein 1B:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the Cryptic family protein 1B:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • Cryptic family protein 1B:ALK1 heteromultimers are soluble.
  • a Cryptic family protein 1B:ALK1 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and ALK1 homomultimers).
  • a Cryptic family protein 1B:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • the Cryptic family protein 1B:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the Cryptic family protein 1B:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • Cryptic family protein 1B:ALK2 heteromultimers are soluble.
  • a Cryptic family protein 1B:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and ALK2 homomultimers).
  • a Cryptic family protein 1B:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • the Cryptic family protein 1B:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the Cryptic family protein 1B:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • Cryptic family protein 1B:ALK3 heteromultimers are soluble.
  • a Cryptic family protein 1B:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and ALK3 homomultimers).
  • a Cryptic family protein 1B:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • the Cryptic family protein 1B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the Cryptic family protein 1B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the Cryptic family protein 1B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • Cryptic family protein 1B:ALK4 heteromultimers are soluble.
  • a Cryptic family protein 1B:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and ALK4 homomultimers).
  • a Cryptic family protein 1B:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • the Cryptic family protein 1B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the Cryptic family protein 1B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the Cryptic family protein 1B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • Cryptic family protein 1B:ALK5 heteromultimers are soluble.
  • a Cryptic family protein 1B:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and ALK5 homomultimers).
  • a Cryptic family protein 1B:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • the Cryptic family protein 1B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the Cryptic family protein 1B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the Cryptic family protein 1B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • Cryptic family protein 1B:ALK6 heteromultimers are soluble.
  • a Cryptic family protein 1B:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and ALK6 homomultimers).
  • a Cryptic family protein 1B:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • the Cryptic family protein 1B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the Cryptic family protein 1B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the Cryptic family protein 1B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the Cryptic family protein 1B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the Cryptic family protein 1B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • Cryptic family protein 1B:ALK7 heteromultimers are soluble.
  • a Cryptic family protein 1B:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and ALK7 homomultimers).
  • a Cryptic family protein 1B:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • the Crim1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • the Crim1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the Crim1:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • Crim1:ALK1 heteromultimers are soluble.
  • a Crim1:ALK1 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and ALK1 homomultimers).
  • a Crim1:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • the Crim1:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the Crim1:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • Crim1:ALK2 heteromultimers are soluble.
  • a Crim1:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and ALK2 homomultimers).
  • a Crim1:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • the Crim1:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the Crim1:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • Crim1:ALK3 heteromultimers are soluble.
  • a Crim1:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and ALK3 homomultimers).
  • a Crim1:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • the Crim1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the Crim1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the Crim1:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • Crim1:ALK4 heteromultimers are soluble.
  • a Crim1:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and ALK4 homomultimers).
  • a Crim1:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • the Crim1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the Crim1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the Crim1:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • Crim1:ALK5 heteromultimers are soluble.
  • a Crim1:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and ALK5 homomultimers).
  • a Crim1:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • the Crim1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the Crim1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the Crim1:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • Crim1:ALK6 heteromultimers are soluble.
  • a Crim1:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and ALK6 homomultimers).
  • a Crim1:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • the Crim1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the Crim1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the Crim1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the Crim1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the Crim1:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • Crim1:ALK7 heteromultimers are soluble.
  • a Crim1:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and ALK7 homomultimers).
  • a Crim1:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim2 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim2:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 541, 542, 545, or 546.
  • the Crim2:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-138 of SEQ ID NO: 541 and ends at any one of amino acids 1298-1503 of SEQ ID NO: 541.
  • the Crim2:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-138 of SEQ ID NO: 545 and ends at any one of amino acids 539-814 of SEQ ID NO: 545.
  • the Crim2:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the Crim2:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • Crim2:ALK1 heteromultimers are soluble.
  • a Crim2:ALK1 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim2:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim2:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim2 and ALK1 homomultimers).
  • a Crim2:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim2 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim2:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 541, 542, 545, or 546.
  • the Crim2:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-138 of SEQ ID NO: 541 and ends at any one of amino acids 1298-1503 of SEQ ID NO: 541.
  • the Crim2:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-138 of SEQ ID NO: 545 and ends at any one of amino acids 539-814 of SEQ ID NO: 545.
  • the Crim2:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the Crim2:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • Crim2:ALK2 heteromultimers are soluble.
  • a Crim2:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim2:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim2:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim2 and ALK2 homomultimers).
  • a Crim2:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim2 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim2:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 541, 542, 545, or 546.
  • the Crim2:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-138 of SEQ ID NO: 541 and ends at any one of amino acids 1298-1503 of SEQ ID NO: 541.
  • the Crim2:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-138 of SEQ ID NO: 545 and ends at any one of amino acids 539-814 of SEQ ID NO: 545.
  • the Crim2:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 541, 542, 545, or 546.
  • the Crim2:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-138 of SEQ ID NO: 541 and ends at any one of amino acids 1298-1503 of SEQ ID NO: 541.
  • the Crim2:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-138 of SEQ ID NO: 545 and ends at any one of amino acids 539-814 of SEQ ID NO: 545.
  • Crim2:ALK3 heteromultimers are soluble.
  • a Crim2:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim2:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim2:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim2 and ALK3 homomultimers).
  • a Crim2:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim2 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim2:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 541, 542, 545, or 546.
  • the Crim2:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-138 of SEQ ID NO: 541 and ends at any one of amino acids 1298-1503 of SEQ ID NO: 541.
  • the Crim2:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-138 of SEQ ID NO: 545 and ends at any one of amino acids 539-814 of SEQ ID NO: 545.
  • the Crim2:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the Crim2:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the Crim2:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • Crim2:ALK4 heteromultimers are soluble.
  • a Crim2:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim2:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim2:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim2 and ALK4 homomultimers).
  • a Crim2:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim2 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim2:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 541, 542, 545, or 546.
  • the Crim2:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-138 of SEQ ID NO: 541 and ends at any one of amino acids 1298-1503 of SEQ ID NO: 541.
  • the Crim2:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-138 of SEQ ID NO: 545 and ends at any one of amino acids 539-814 of SEQ ID NO: 545.
  • the Crim2:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the Crim2:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the Crim2:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • Crim2:ALK5 heteromultimers are soluble.
  • a Crim2:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim2:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim2:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim2 and ALK5 homomultimers).
  • a Crim2:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim2 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim2:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 541, 542, 545, or 546.
  • the Crim2:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-138 of SEQ ID NO: 541 and ends at any one of amino acids 1298-1503 of SEQ ID NO: 541.
  • the Crim2:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-138 of SEQ ID NO: 545 and ends at any one of amino acids 539-814 of SEQ ID NO: 545.
  • the Crim2:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the Crim2:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the Crim2:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • Crim2:ALK6 heteromultimers are soluble.
  • a Crim2:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim2:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim2:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim2 and ALK6 homomultimers).
  • a Crim2:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim2 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim2:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 541, 542, 545, or 546.
  • the Crim2:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-138 of SEQ ID NO: 541 and ends at any one of amino acids 1298-1503 of SEQ ID NO: 541.
  • the Crim2:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-138 of SEQ ID NO: 545 and ends at any one of amino acids 539-814 of SEQ ID NO: 545.
  • the Crim2:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the Crim2:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the Crim2:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the Crim2:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the Crim2:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • Crim2:ALK7 heteromultimers are soluble.
  • a Crim2:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim2:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim2:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim2 and ALK7 homomultimers).
  • a Crim2:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BAMBI polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BAMBI:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 549 or 550.
  • the BAMBI:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 549 and ends at any one of amino acids 104-152 of SEQ ID NO: 549.
  • the BAMBI:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the BAMBI:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • BAMBI:ALK1 heteromultimers are soluble.
  • a BAMBI:ALK1 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BAMBI:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BAMBI:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BAMBI and ALK1 homomultimers).
  • a BAMBI:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BAMBI polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BAMBI:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 549 or 550.
  • the BAMBI:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 549 and ends at any one of amino acids 104-152 of SEQ ID NO: 549.
  • the BAMBI:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the BAMBI:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • BAMBI:ALK2 heteromultimers are soluble.
  • a BAMBI:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BAMBI:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BAMBI:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BAMBI and ALK2 homomultimers).
  • a BAMBI:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BAMBI polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BAMBI:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 549 or 550.
  • the BAMBI:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 549 and ends at any one of amino acids 104-152 of SEQ ID NO: 549.
  • the BAMBI:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the BAMBI:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • BAMBI:ALK3 heteromultimers are soluble.
  • a BAMBI:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BAMBI:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BAMBI:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BAMBI and ALK3 homomultimers).
  • a BAMBI:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BAMBI polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BAMBI:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 549 or 550.
  • the BAMBI:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 549 and ends at any one of amino acids 104-152 of SEQ ID NO: 549.
  • the BAMBI:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the BAMBI:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the BAMBI:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • BAMBI:ALK4 heteromultimers are soluble.
  • a BAMBI:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BAMBI:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BAMBI:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BAMBI and ALK4 homomultimers).
  • a BAMBI:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BAMBI polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BAMBI:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 549 or 550.
  • the BAMBI:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 549 and ends at any one of amino acids 104-152 of SEQ ID NO: 549.
  • the BAMBI:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the BAMBI:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the BAMBI:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • BAMBI:ALK5 heteromultimers are soluble.
  • a BAMBI:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BAMBI:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BAMBI:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BAMBI and ALK5 homomultimers).
  • a BAMBI:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BAMBI polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BAMBI:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 549 or 550.
  • the BAMBI:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 549 and ends at any one of amino acids 104-152 of SEQ ID NO: 549.
  • the BAMBI:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the BAMBI:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the BAMBI:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • BAMBI:ALK6 heteromultimers are soluble.
  • a BAMBI:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BAMBI:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BAMBI:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BAMBI and ALK6 homomultimers).
  • a BAMBI:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BAMBI polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BAMBI:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 549 or 550.
  • the BAMBI:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 549 and ends at any one of amino acids 104-152 of SEQ ID NO: 549.
  • the BAMBI:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the BAMBI:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the BAMBI:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the BAMBI:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the BAMBI:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • BAMBI:ALK7 heteromultimers are soluble.
  • a BAMBI:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BAMBI:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BAMBI:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BAMBI and ALK7 homomultimers).
  • a BAMBI:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BMPER polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BMPER:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the BMPER:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553.
  • the BMPER:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK1 heteromultimer comprises a BMPER protein, wherein the BMPER protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553, and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER protein is a dimer comprising a first polypeptide that is at least
  • the BMPER:ALK1 heteromultimer comprises a single chain ligand trap that comprises a first BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the BMPER:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • BMPER:ALK1 heteromultimers are soluble.
  • a BMPER:ALK1 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BMPER:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BMPER:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BMPER and ALK1 homomultimers).
  • a BMPER:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BMPER polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BMPER:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the BMPER:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553.
  • the BMPER:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK2 heteromultimer comprises a BMPER protein, wherein the BMPER protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553, and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER protein is a dimer comprising a first polypeptide that is at least
  • the BMPER:ALK2 heteromultimer comprises a single chain ligand trap that comprises a first BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the BMPER:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • BMPER:ALK2 heteromultimers are soluble.
  • a BMPER:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BMPER:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BMPER:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BMPER and ALK2 homomultimers).
  • a BMPER:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BMPER polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BMPER:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the BMPER:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553.
  • the BMPER:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK3 heteromultimer comprises a BMPER protein, wherein the BMPER protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553, and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER protein is a dimer comprising a first polypeptide that is at least
  • the BMPER:ALK3 heteromultimer comprises a single chain ligand trap that comprises a first BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the BMPER:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • BMPER:ALK3 heteromultimers are soluble.
  • a BMPER:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BMPER:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BMPER:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BMPER and ALK3 homomultimers).
  • a BMPER:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BMPER polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BMPER:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the BMPER:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553.
  • the BMPER:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK4 heteromultimer comprises a BMPER protein, wherein the BMPER protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553, and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER protein is a dimer comprising a first polypeptide that is at least
  • the BMPER:ALK4 heteromultimer comprises a single chain ligand trap that comprises a first BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the BMPER:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the BMPER:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • BMPER:ALK4 heteromultimers are soluble.
  • a BMPER:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BMPER:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BMPER:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BMPER and ALK4 homomultimers).
  • a BMPER:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BMPER polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BMPER:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the BMPER:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553.
  • the BMPER:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK5 heteromultimer comprises a BMPER protein, wherein the BMPER protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553, and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER protein is a dimer comprising a first polypeptide that is at least
  • the BMPER:ALK5 heteromultimer comprises a single chain ligand trap that comprises a first BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the BMPER:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the BMPER:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • BMPER:ALK5 heteromultimers are soluble.
  • a BMPER:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BMPER:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BMPER:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BMPER and ALK5 homomultimers).
  • a BMPER:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BMPER polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BMPER:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the BMPER:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553.
  • the BMPER:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK6 heteromultimer comprises a BMPER protein, wherein the BMPER protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553, and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER protein is a dimer comprising a first polypeptide that is at least
  • the BMPER:ALK6 heteromultimer comprises a single chain ligand trap that comprises a first BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the BMPER:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the BMPER:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • BMPER:ALK6 heteromultimers are soluble.
  • a BMPER:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BMPER:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BMPER:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BMPER and ALK6 homomultimers).
  • a BMPER:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one BMPER polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the BMPER:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the BMPER:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553.
  • the BMPER:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK7 heteromultimer comprises a BMPER protein, wherein the BMPER protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553, and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER protein is a dimer comprising a first polypeptide that is at least
  • the BMPER:ALK7 heteromultimer comprises a single chain ligand trap that comprises a first BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 39-50 of SEQ ID NO: 553 and ends at any one of amino acids 364-369 of SEQ ID NO: 553, and second BMPER polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 370-386 of SEQ ID NO: 553 and ends at any one of amino acids 682-685 of SEQ ID NO: 553.
  • the BMPER:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the BMPER:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the BMPER:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the BMPER:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the BMPER:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • BMPER:ALK7 heteromultimers are soluble.
  • a BMPER:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a BMPER:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a BMPER:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., BMPER and ALK7 homomultimers).
  • a BMPER:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-A polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-A:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the RGM-A:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-177 of SEQ ID NO: 561 and ends at any one of amino acids 430-458 of SEQ ID NO: 561.
  • the RGM-A:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-153 of SEQ ID NO: 565 and ends at any one of amino acids 406-434 of SEQ ID NO: 565.
  • the RGM-A:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-169 of SEQ ID NO: 569 and ends at any one of amino acids 422-450 of SEQ ID NO: 569.
  • the RGM-A:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the RGM-A:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • RGM-A:ALK1 heteromultimers are soluble.
  • a RGM-A:ALK heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-A:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-A:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-A and ALK1 homomultimers).
  • a RGM-A:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-A polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-A:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the RGM-A:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-177 of SEQ ID NO: 561 and ends at any one of amino acids 430-458 of SEQ ID NO: 561.
  • the RGM-A:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-153 of SEQ ID NO: 565 and ends at any one of amino acids 406-434 of SEQ ID NO: 565.
  • the RGM-A:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-169 of SEQ ID NO: 569 and ends at any one of amino acids 422-450 of SEQ ID NO: 569.
  • the RGM-A:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the RGM-A:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • RGM-A:ALK2 heteromultimers are soluble.
  • a RGM-A:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-A:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-A:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-A and ALK2 homomultimers).
  • a RGM-A:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-A polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-A:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the RGM-A:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-177 of SEQ ID NO: 561 and ends at any one of amino acids 430-458 of SEQ ID NO: 561.
  • the RGM-A:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-153 of SEQ ID NO: 565 and ends at any one of amino acids 406-434 of SEQ ID NO: 565.
  • the RGM-A:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-169 of SEQ ID NO: 569 and ends at any one of amino acids 422-450 of SEQ ID NO: 569.
  • the RGM-A:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the RGM-A:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • RGM-A:ALK3 heteromultimers are soluble.
  • a RGM-A:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-A:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-A:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-A and ALK3 homomultimers).
  • a RGM-A:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-A polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-A:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the RGM-A:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-177 of SEQ ID NO: 561 and ends at any one of amino acids 430-458 of SEQ ID NO: 561.
  • the RGM-A:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-153 of SEQ ID NO: 565 and ends at any one of amino acids 406-434 of SEQ ID NO: 565.
  • the RGM-A:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-169 of SEQ ID NO: 569 and ends at any one of amino acids 422-450 of SEQ ID NO: 569.
  • the RGM-A:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the RGM-A:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the RGM-A:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • RGM-A:ALK4 heteromultimers are soluble.
  • a RGM-A:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-A:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-A:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-A and ALK4 homomultimers).
  • a RGM-A:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-A polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-A:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the RGM-A:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-177 of SEQ ID NO: 561 and ends at any one of amino acids 430-458 of SEQ ID NO: 561.
  • the RGM-A:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-153 of SEQ ID NO: 565 and ends at any one of amino acids 406-434 of SEQ ID NO: 565.
  • the RGM-A:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-169 of SEQ ID NO: 569 and ends at any one of amino acids 422-450 of SEQ ID NO: 569.
  • the RGM-A:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the RGM-A:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the RGM-A:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • RGM-A:ALK5 heteromultimers are soluble.
  • a RGM-A:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-A:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-A:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-A and ALK5 homomultimers).
  • a RGM-A:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-A polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-A:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the RGM-A:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-177 of SEQ ID NO: 561 and ends at any one of amino acids 430-458 of SEQ ID NO: 561.
  • the RGM-A:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-153 of SEQ ID NO: 565 and ends at any one of amino acids 406-434 of SEQ ID NO: 565.
  • the RGM-A:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-169 of SEQ ID NO: 569 and ends at any one of amino acids 422-450 of SEQ ID NO: 569.
  • the RGM-A:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the RGM-A:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-177 of SEQ ID NO: 561 and ends at any one of amino acids 430-458 of SEQ ID NO: 561.
  • the RGM-A:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-153 of SEQ ID NO: 565 and ends at any one of amino acids 406-434 of SEQ ID NO: 565.
  • the RGM-A:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-169 of SEQ ID NO: 569 and ends at any one of amino acids 422-450 of SEQ ID NO: 569.
  • RGM-A:ALK6 heteromultimers are soluble.
  • a RGM-A:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-A:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-A:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-A and ALK6 homomultimers).
  • a RGM-A:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-A polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-A:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 553 or 554.
  • the RGM-A:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-177 of SEQ ID NO: 561 and ends at any one of amino acids 430-458 of SEQ ID NO: 561.
  • the RGM-A:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-153 of SEQ ID NO: 565 and ends at any one of amino acids 406-434 of SEQ ID NO: 565.
  • the RGM-A:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-169 of SEQ ID NO: 569 and ends at any one of amino acids 422-450 of SEQ ID NO: 569.
  • the RGM-A:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the RGM-A:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the RGM-A:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the RGM-A:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the RGM-A:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • RGM-A:ALK7 heteromultimers are soluble.
  • a RGM-A:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-A:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-A:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-A and ALK7 homomultimers).
  • a RGM-A:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-B:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 557 or 558.
  • the RGM-B:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-87 of SEQ ID NO: 557 and ends at any one of amino acids 452-478 of SEQ ID NO: 557.
  • the RGM-B:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557.
  • the RGM-B:ALK1 heteromultimer comprises a RGM-B protein, wherein the RGM-B protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B protein is a dimer comprising a first
  • the RGM-B:ALK1 heteromultimer comprises a single chain ligand trap that comprises a first RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the RGM-B:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • RGM-B:ALK1 heteromultimers are soluble.
  • a RGM-B:ALK1 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-B:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-B:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-B and ALK1 homomultimers).
  • a RGM-B:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-B:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 557 or 558.
  • the RGM-B:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-87 of SEQ ID NO: 557 and ends at any one of amino acids 452-478 of SEQ ID NO: 557.
  • the RGM-B:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557.
  • the RGM-B:ALK2 heteromultimer comprises a RGM-B protein, wherein the RGM-B protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B protein is a dimer comprising a first
  • the RGM-B:ALK2 heteromultimer comprises a single chain ligand trap that comprises a first RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the RGM-B:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • RGM-B:ALK2 heteromultimers are soluble.
  • a RGM-B:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-B:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-B:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-B and ALK2 homomultimers).
  • a RGM-B:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-B:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 557 or 558.
  • the RGM-B:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-87 of SEQ ID NO: 557 and ends at any one of amino acids 452-478 of SEQ ID NO: 557.
  • the RGM-B:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557.
  • the RGM-B:ALK3 heteromultimer comprises a RGM-B protein, wherein the RGM-B protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B protein is a dimer comprising a first
  • the RGM-B:ALK3 heteromultimer comprises a single chain ligand trap that comprises a first RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the RGM-B:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • RGM-B:ALK3 heteromultimers are soluble.
  • a RGM-B:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-B:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-B:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-B and ALK3 homomultimers).
  • a RGM-B:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 557 or 558.
  • the RGM-B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-87 of SEQ ID NO: 557 and ends at any one of amino acids 452-478 of SEQ ID NO: 557.
  • the RGM-B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557.
  • the RGM-B:ALK4 heteromultimer comprises a RGM-B protein, wherein the RGM-B protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B protein is a dimer comprising a first
  • the RGM-B:ALK4 heteromultimer comprises a single chain ligand trap that comprises a first RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the RGM-B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the RGM-B:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • RGM-B:ALK4 heteromultimers are soluble.
  • a RGM-B:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-B:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-B:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-B and ALK4 homomultimers).
  • a RGM-B:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 557 or 558.
  • the RGM-B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-87 of SEQ ID NO: 557 and ends at any one of amino acids 452-478 of SEQ ID NO: 557.
  • the RGM-B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557.
  • the RGM-B:ALK5 heteromultimer comprises a RGM-B protein, wherein the RGM-B protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B protein is a dimer comprising a first
  • the RGM-B:ALK5 heteromultimer comprises a single chain ligand trap that comprises a first RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the RGM-B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the RGM-B:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • RGM-B:ALK5 heteromultimers are soluble.
  • a RGM-B:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-B:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-B:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-B and ALK5 homomultimers).
  • a RGM-B:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 557 or 558.
  • the RGM-B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-87 of SEQ ID NO: 557 and ends at any one of amino acids 452-478 of SEQ ID NO: 557.
  • the RGM-B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557.
  • the RGM-B:ALK6 heteromultimer comprises a RGM-B protein, wherein the RGM-B protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B protein is a dimer comprising a first
  • the RGM-B:ALK6 heteromultimer comprises a single chain ligand trap that comprises a first RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the RGM-B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the RGM-B:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • RGM-B:ALK6 heteromultimers are soluble.
  • a RGM-B:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-B:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-B:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-B and ALK6 homomultimers).
  • a RGM-B:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one RGM-B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the RGM-B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 557 or 558.
  • the RGM-B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-87 of SEQ ID NO: 557 and ends at any one of amino acids 452-478 of SEQ ID NO: 557.
  • the RGM-B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557.
  • the RGM-B:ALK7 heteromultimer comprises a RGM-B protein, wherein the RGM-B protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B protein is a dimer comprising a first
  • the RGM-B:ALK7 heteromultimer comprises a single chain ligand trap that comprises a first RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 87-95 of SEQ ID NO: 557 and ends at any one of amino acids 204-209 of SEQ ID NO: 557 and second RGM-B polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 210-222 of SEQ ID NO: 557 and ends at any one of amino acids 413-452 of SEQ ID NO: 557.
  • the RGM-B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the RGM-B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the RGM-B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the RGM-B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the RGM-B:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • RGM-B:ALK7 heteromultimers are soluble.
  • a RGM-B:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a RGM-B:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a RGM-B:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., RGM-B and ALK7 homomultimers).
  • a RGM-B:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one hemojuvelin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK1 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the hemojuvelin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 573, 574, 577, 578, 581, or 582.
  • the hemojuvelin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-36 of SEQ ID NO: 573 and ends at any one of amino acids 400-426 of SEQ ID NO: 573.
  • the hemojuvelin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573.
  • the hemojuvelin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK1 heteromultimer comprises a hemojuvelin protein that is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573, and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK1 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 287-313 of SEQ ID NO: 577.
  • the hemojuvelin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577.
  • the hemojuvelin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK1 heteromultimer comprises a hemojuvelin protein, wherein the hemojuvelin protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin protein is a dimer comprising a first polypeptide
  • the hemojuvelin:ALK1 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577, and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-4 of SEQ ID NO: 581 and ends at any one of amino acids 135-200 of SEQ ID NO: 581.
  • the hemojuvelin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 14 or 15.
  • the hemojuvelin:ALK1 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 22-34 of SEQ ID NO: 14 and ends at any one of amino acids 95-118 of SEQ ID NO: 14.
  • hemojuvelin:ALK1 heteromultimers are soluble.
  • a hemojuvelin:ALK heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a hemojuvelin:ALK1 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a hemojuvelin:ALK1 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., hemojuvelin and ALK1 homomultimers).
  • a hemojuvelin:ALK1 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one hemojuvelin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK2 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the hemojuvelin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 573, 574, 577, 578, 581, or 582.
  • the hemojuvelin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-36 of SEQ ID NO: 573 and ends at any one of amino acids 400-426 of SEQ ID NO: 573.
  • the hemojuvelin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573.
  • the hemojuvelin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK2 heteromultimer comprises a hemojuvelin protein that is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573, and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK2 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 287-313 of SEQ ID NO: 577.
  • the hemojuvelin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577.
  • the hemojuvelin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK2 heteromultimer comprises a hemojuvelin protein, wherein the hemojuvelin protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin protein is a dimer comprising a first polypeptide
  • the hemojuvelin:ALK2 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577, and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-4 of SEQ ID NO: 581 and ends at any one of amino acids 135-200 of SEQ ID NO: 581.
  • the hemojuvelin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 18 or 19.
  • the hemojuvelin:ALK2 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-35 of SEQ ID NO: 18 and ends at any one of amino acids 99-123 of SEQ ID NO: 18.
  • hemojuvelin:ALK2 heteromultimers are soluble.
  • a hemojuvelin:ALK2 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a hemojuvelin:ALK2 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a hemojuvelin:ALK2 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., hemojuvelin and ALK2 homomultimers).
  • a hemojuvelin:ALK2 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one hemojuvelin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK3 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the hemojuvelin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 573, 574, 577, 578, 581, or 582.
  • the hemojuvelin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-36 of SEQ ID NO: 573 and ends at any one of amino acids 400-426 of SEQ ID NO: 573.
  • the hemojuvelin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573.
  • the hemojuvelin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK3 heteromultimer comprises a hemojuvelin protein that is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573, and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK3 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 287-313 of SEQ ID NO: 577.
  • the hemojuvelin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577.
  • the hemojuvelin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK3 heteromultimer comprises a hemojuvelin protein, wherein the hemojuvelin protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin protein is a dimer comprising a first polypeptide
  • the hemojuvelin:ALK3 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577, and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-4 of SEQ ID NO: 581 and ends at any one of amino acids 135-200 of SEQ ID NO: 581.
  • the hemojuvelin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 22 or 23.
  • the hemojuvelin:ALK3 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-61 of SEQ ID NO: 22 and ends at any one of amino acids 130-152 of SEQ ID NO: 22.
  • hemojuvelin:ALK3 heteromultimers are soluble.
  • a hemojuvelin:ALK3 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a hemojuvelin:ALK3 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a hemojuvelin:ALK3 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., hemojuvelin and ALK3 homomultimers).
  • a hemojuvelin:ALK3 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one hemojuvelin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK4 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 573, 574, 577, 578, 581, or 582.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-36 of SEQ ID NO: 573 and ends at any one of amino acids 400-426 of SEQ ID NO: 573.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK4 heteromultimer comprises a hemojuvelin protein that is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573, and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK4 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 287-313 of SEQ ID NO: 577.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK4 heteromultimer comprises a hemojuvelin protein, wherein the hemojuvelin protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin protein is a dimer comprising a first polypeptide
  • the hemojuvelin:ALK4 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577, and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-4 of SEQ ID NO: 581 and ends at any one of amino acids 135-200 of SEQ ID NO: 581.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 26, 27, 83, or 84.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 26 and ends at any one of amino acids 101-126 of SEQ ID NO: 26.
  • the hemojuvelin:ALK4 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-34 of SEQ ID NO: 83 and ends at any one of amino acids 101-126 of SEQ ID NO: 83.
  • hemojuvelin:ALK4 heteromultimers are soluble.
  • a hemojuvelin:ALK4 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a hemojuvelin:ALK4 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a hemojuvelin:ALK4 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., hemojuvelin and ALK4 homomultimers).
  • a hemojuvelin:ALK4 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one hemojuvelin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK5 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 573, 574, 577, 578, 581, or 582.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-36 of SEQ ID NO: 573 and ends at any one of amino acids 400-426 of SEQ ID NO: 573.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK5 heteromultimer comprises a hemojuvelin protein that is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573, and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK5 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 287-313 of SEQ ID NO: 577.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK5 heteromultimer comprises a hemojuvelin protein, wherein the hemojuvelin protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin protein is a dimer comprising a first polypeptide
  • the hemojuvelin:ALK5 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577, and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-4 of SEQ ID NO: 581 and ends at any one of amino acids 135-200 of SEQ ID NO: 581.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 30, 31, 87, or 88.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 30 and ends at any one of amino acids 101-126 of SEQ ID NO: 30.
  • the hemojuvelin:ALK5 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 25-36 of SEQ ID NO: 87 and ends at any one of amino acids 101-130 of SEQ ID NO: 87.
  • hemojuvelin:ALK5 heteromultimers are soluble.
  • a hemojuvelin:ALK5 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a hemojuvelin:ALK5 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a hemojuvelin:ALK5 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., hemojuvelin and ALK5 homomultimers).
  • a hemojuvelin:ALK5 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one hemojuvelin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK6 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 573, 574, 577, 578, 581, or 582.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-36 of SEQ ID NO: 573 and ends at any one of amino acids 400-426 of SEQ ID NO: 573.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK6 heteromultimer comprises a hemojuvelin protein that is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573, and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK6 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 287-313 of SEQ ID NO: 577.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK6 heteromultimer comprises a hemojuvelin protein, wherein the hemojuvelin protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin protein is a dimer comprising a first polypeptide
  • the hemojuvelin:ALK6 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577, and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-4 of SEQ ID NO: 581 and ends at any one of amino acids 135-200 of SEQ ID NO: 581.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 34, 35, 91, or 92.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 14-32 of SEQ ID NO: 34 and ends at any one of amino acids 102-126 of SEQ ID NO: 34.
  • the hemojuvelin:ALK6 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-62 of SEQ ID NO: 91 and ends at any one of amino acids 132-156 of SEQ ID NO: 91.
  • hemojuvelin:ALK6 heteromultimers are soluble.
  • a hemojuvelin:ALK6 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a hemojuvelin:ALK6 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a hemojuvelin:ALK6 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., hemojuvelin and ALK6 homomultimers).
  • a hemojuvelin:ALK6 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one hemojuvelin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ALK7 polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 573, 574, 577, 578, 581, or 582.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-36 of SEQ ID NO: 573 and ends at any one of amino acids 400-426 of SEQ ID NO: 573.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK7 heteromultimer comprises a hemojuvelin protein that is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573, and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK7 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 36-42 of SEQ ID NO: 573 and ends at any one of amino acids 167-172 of SEQ ID NO: 573 and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 173-185 of SEQ ID NO: 573 and ends at any one of amino acids 361-400 of SEQ ID NO: 573.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 287-313 of SEQ ID NO: 577.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK7 heteromultimer comprises a hemojuvelin protein, wherein the hemojuvelin protein is a dimer comprising a first polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577 and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin protein is a dimer comprising a first polypeptide
  • the hemojuvelin:ALK7 heteromultimer comprises a single chain ligand trap that comprises a first hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-6 of SEQ ID NO: 577 and ends at any one of amino acids 54-59 of SEQ ID NO: 577, and second hemojuvelin polypeptide domain that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 60-72 of SEQ ID NO: 577, and ends at any one of amino acids 248-287 of SEQ ID NO: 577.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-4 of SEQ ID NO: 581 and ends at any one of amino acids 135-200 of SEQ ID NO: 581.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: SEQ ID NO: 38, 39, 301, 302, 305, 306, 309, 310, or 313.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 38 and ends at any one of amino acids 92-113 of SEQ ID NO: 38.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-13 of SEQ ID NO: 301 and ends at any one of amino acids 42-63 of SEQ ID NO: 301.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 305 and ends at any one of amino acids 411-413 of SEQ ID NO: 305.
  • the hemojuvelin:ALK7 heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 309 and ends at any one of amino acids 334-336 of SEQ ID NO: 309.
  • hemojuvelin:ALK7 heteromultimers are soluble.
  • a hemojuvelin:ALK7 heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a hemojuvelin:ALK7 heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a hemojuvelin:ALK7 heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., hemojuvelin and ALK7 homomultimers).
  • a hemojuvelin:ALK7 heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIA polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • a endoglin:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 9, 10, and 11.
  • a endoglin:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 9, and ends at any one of amino acids 110-135 of SEQ ID NO: 9.
  • endoglin:ActRIIA heteromultimers are soluble.
  • a endoglin:ActRIIA heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a endoglin:ActRIIA heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a endoglin:ActRIIA heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and ActRIIA homomultimers).
  • a endoglin:ActRIIA heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIB polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • a endoglin:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.
  • a endoglin:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids 20-29 of SEQ ID NO: 1 and ends at a position corresponding to any one of amino acids 109-134 of SEQ ID NO: 1.
  • a endoglin:ActRIIB heteromultimer comprises an ActRIIB polypeptide wherein the amino acid position corresponding to L79 of SEQ ID NO: 1 is not an acidic amino acid.
  • endoglin:ActRIIB heteromultimers are soluble.
  • a endoglin:ActRIIB heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a endoglin:ActRIIB heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a endoglin:ActRIIB heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and ActRIIB homomultimers).
  • a endoglin:ActRIIB heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one TGFBRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • a endoglin:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 42, 43, 67, or 68.
  • a endoglin:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-51 of SEQ ID NO: 42 and ends at any one of amino acids 143-166 of SEQ ID NO: 42.
  • a endoglin:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-44 of SEQ ID NO: 67 and ends at any one of amino acids 168-191 of SEQ ID NO: 67.
  • endoglin:TGFBRII heteromultimers are soluble.
  • a endoglin:TGFBRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a endoglin:TGFBRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a endoglin:TGFBRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and TGFBRII homomultimers).
  • a endoglin:TGFBRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one BMPRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • a endoglin:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 46, 47, 71, or 72.
  • a endoglin:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 46 and ends at any one of amino acids 123-150 of SEQ ID NO: 46.
  • a endoglin:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 71 and ends at any one of amino acids 123-150 of SEQ ID NO: 71.
  • endoglin:BMPRII heteromultimers are soluble.
  • a endoglin:BMPRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a endoglin:BMPRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a endoglin:BMPRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and BMPRII homomultimers).
  • a endoglin:BMPRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one endoglin polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one MISRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the endoglin:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 501, 502, 505, 506, 509, 510, 593, or 594.
  • the endoglin:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 501 and ends at any one of amino acids 330-346 of SEQ ID NO: 501.
  • the endoglin:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 505 and ends at any one of amino acids 330-346 of SEQ ID NO: 505.
  • the endoglin:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 1-25 of SEQ ID NO: 509, and ends at any one of amino acids 148-164 of SEQ ID NO: 509.
  • a endoglin:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 50, 51, 75, 76, 79, or 80.
  • a endoglin:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 50.
  • a endoglin:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 75 and ends at any one of amino acids 116-149 of SEQ ID NO: 75.
  • a endoglin:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 79.
  • endoglin:MISRII heteromultimers are soluble.
  • a endoglin:MISRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a endoglin:MISRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a endoglin:MISRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., endoglin and MISRII homomultimers).
  • a endoglin:MISRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIA polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • a betaglycan:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 9, 10, and 11.
  • a betaglycan:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 9, and ends at any one of amino acids 110-135 of SEQ ID NO: 9.
  • betaglycan:ActRIIA heteromultimers are soluble.
  • a betaglycan:ActRIIA heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a betaglycan:ActRIIA heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a betaglycan:ActRIIA heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and ActRIIA homomultimers).
  • a betaglycan:ActRIIA heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIB polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • a betaglycan:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.
  • a betaglycan:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids 20-29 of SEQ ID NO: 1 and ends at a position corresponding to any one of amino acids 109-134 of SEQ ID NO: 1.
  • a betaglycan:ActRIIB heteromultimer comprises an ActRIIB polypeptide wherein the amino acid position corresponding to L79 of SEQ ID NO: 1 is not an acidic amino acid.
  • betaglycan:ActRIIB heteromultimers are soluble.
  • a betaglycan:ActRIIB heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a betaglycan:ActRIIB heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a betaglycan:ActRIIB heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and ActRIIB homomultimers).
  • a betaglycan:ActRIIB heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one TGFBRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • a betaglycan:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 42, 43, 67, or 68.
  • a betaglycan:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-51 of SEQ ID NO: 42 and ends at any one of amino acids 143-166 of SEQ ID NO: 42.
  • a betaglycan:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-44 of SEQ ID NO: 67 and ends at any one of amino acids 168-191 of SEQ ID NO: 67.
  • betaglycan:TGFBRII heteromultimers are soluble.
  • a betaglycan:TGFBRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a betaglycan:TGFBRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a betaglycan:TGFBRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and TGFBRII homomultimers).
  • a betaglycan:TGFBRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one BMPRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • a betaglycan:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 46, 47, 71, or 72.
  • a betaglycan:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 46 and ends at any one of amino acids 123-150 of SEQ ID NO: 46.
  • a betaglycan:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 71 and ends at any one of amino acids 123-150 of SEQ ID NO: 71.
  • betaglycan:BMPRII heteromultimers are soluble.
  • a betaglycan:BMPRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a betaglycan:BMPRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a betaglycan:BMPRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and BMPRII homomultimers).
  • a betaglycan:BMPRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one betaglycan polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one MISRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the betaglycan:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 585, 586, 589, or 590.
  • the betaglycan:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 585 and ends at any one of amino acids 381-787 of SEQ ID NO: 585.
  • the betaglycan:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-28 of SEQ ID NO: 589 and ends at any one of amino acids 380-786 of SEQ ID NO: 589.
  • a betaglycan:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 50, 51, 75, 76, 79, or 80.
  • a betaglycan:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 50.
  • a betaglycan:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 75 and ends at any one of amino acids 116-149 of SEQ ID NO: 75.
  • a betaglycan:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 79.
  • betaglycan:MISRII heteromultimers are soluble.
  • a betaglycan:MISRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a betaglycan:MISRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a betaglycan:MISRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., betaglycan and MISRII homomultimers).
  • a betaglycan:MISRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIA polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • a Cripto-1:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 9, 10, and 11.
  • a Cripto-1:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 9, and ends at any one of amino acids 110-135 of SEQ ID NO: 9.
  • Cripto-1:ActRIIA heteromultimers are soluble.
  • a Cripto-1:ActRIIA heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cripto-1:ActRIIA heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cripto-1:ActRIIA heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and ActRIIA homomultimers).
  • a Cripto-1:ActRIIA heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIB polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • a Cripto-1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.
  • a Cripto-1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids 20-29 of SEQ ID NO: 1 and ends at a position corresponding to any one of amino acids 109-134 of SEQ ID NO: 1.
  • a Cripto-1:ActRIIB heteromultimer comprises an ActRIIB polypeptide wherein the amino acid position corresponding to L79 of SEQ ID NO: 1 is not an acidic amino acid.
  • a Cripto-1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.
  • a Cripto-1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids 20-29 of SEQ ID NO: 1 and ends at a position corresponding to any one of amino acids 109-134 of SEQ ID NO: 1.
  • a Cripto-1:ActRIIB heteromultimer comprises an ActRIIB polypeptide wherein the amino acid position corresponding to L79 of SEQ ID NO: 1 is not an acidic amino acid.
  • Cripto-1:ActRIIB heteromultimers are soluble.
  • a Cripto-1:ActRIIB heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cripto-1:ActRIIB heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cripto-1:ActRIIB heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and ActRIIB homomultimers).
  • a Cripto-1:ActRIIB heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one TGFBRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • a Cripto-1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 42, 43, 67, or 68.
  • a Cripto-1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-51 of SEQ ID NO: 42 and ends at any one of amino acids 143-166 of SEQ ID NO: 42.
  • a Cripto-1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-44 of SEQ ID NO: 67 and ends at any one of amino acids 168-191 of SEQ ID NO: 67.
  • Cripto-1:TGFBRII heteromultimers are soluble.
  • a Cripto-1:TGFBRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cripto-1:TGFBRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling). Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cripto-1:TGFBRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and TGFBRII homomultimers).
  • a Cripto-1:TGFBRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one BMPRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • a Cripto-1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 46, 47, 71, or 72.
  • a Cripto-1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 46 and ends at any one of amino acids 123-150 of SEQ ID NO: 46.
  • a Cripto-1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 71 and ends at any one of amino acids 123-150 of SEQ ID NO: 71.
  • Cripto-1:BMPRII heteromultimers are soluble.
  • a Cripto-1:BMPRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cripto-1:BMPRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cripto-1:BMPRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and BMPRII homomultimers).
  • a Cripto-1:BMPRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cripto-1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one MISRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cripto-1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 513, 514, 517, or 518.
  • the Cripto-1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 31-82 of SEQ ID NO: 513 and ends at any one of amino acids 172-188 of SEQ ID NO: 513.
  • the Cripto-1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 15-66 of SEQ ID NO: 517, and ends at any one of amino acids 156-172 of SEQ ID NO: 517.
  • a Cripto-1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 50, 51, 75, 76, 79, or 80.
  • a Cripto-1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 50.
  • a Cripto-1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 75 and ends at any one of amino acids 116-149 of SEQ ID NO: 75.
  • a Cripto-1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 79.
  • Cripto-1:MISRII heteromultimers are soluble.
  • a Cripto-1:MISRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cripto-1:MISRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling). Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cripto-1:MISRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cripto-1 and MISRII homomultimers).
  • a Cripto-1:MISRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIA polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • a Cryptic protein:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 9, 10, and 11.
  • a Cryptic protein:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 9, and ends at any one of amino acids 110-135 of SEQ ID NO: 9.
  • Cryptic protein:ActRIIA heteromultimers are soluble.
  • a Cryptic protein:ActRIIA heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:ActRIIA heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:ActRIIA heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and ActRIIA homomultimers).
  • a Cryptic protein:ActRIIA heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIB polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • a Cryptic protein:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.
  • a Cryptic protein:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids 20-29 of SEQ ID NO: 1 and ends at a position corresponding to any one of amino acids 109-134 of SEQ ID NO: 1.
  • a Cryptic protein:ActRIIB heteromultimer comprises an ActRIIB polypeptide wherein the amino acid position corresponding to L79 of SEQ ID NO: 1 is not an acidic amino acid.
  • Cryptic protein:ActRIIB heteromultimers are soluble.
  • a Cryptic protein:ActRIIB heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:ActRIIB heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:ActRIIB heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and ActRIIB homomultimers).
  • a Cryptic protein:ActRIIB heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one TGFBRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • a Cryptic protein:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 42, 43, 67, or 68.
  • a Cryptic protein:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-51 of SEQ ID NO: 42 and ends at any one of amino acids 143-166 of SEQ ID NO: 42.
  • a Cryptic protein:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-44 of SEQ ID NO: 67 and ends at any one of amino acids 168-191 of SEQ ID NO: 67.
  • Cryptic protein:TGFBRII heteromultimers are soluble.
  • a Cryptic protein:TGFBRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:TGFBRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:TGFBRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and TGFBRII homomultimers).
  • a Cryptic protein:TGFBRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one BMPRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • a Cryptic protein:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 46, 47, 71, or 72.
  • a Cryptic protein:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 46 and ends at any one of amino acids 123-150 of SEQ ID NO: 46.
  • a Cryptic protein:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 71 and ends at any one of amino acids 123-150 of SEQ ID NO: 71.
  • Cryptic protein:BMPRII heteromultimers are soluble.
  • a Cryptic protein:BMPRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:BMPRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:BMPRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and BMPRII homomultimers).
  • a Cryptic protein:BMPRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic protein polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one MISRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic protein:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 521, 522, 525, 526, 529, or 530.
  • the Cryptic protein:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-90 of SEQ ID NO: 521 and ends at any one of amino acids 157-233 of SEQ ID NO: 521.
  • the Cryptic protein:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 525 and ends at any one of amino acids 82-191 of SEQ ID NO: 525.
  • the Cryptic protein:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 529, and ends at any one of amino acids 82-148 of SEQ ID NO: 529.
  • a Cryptic protein:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 50, 51, 75, 76, 79, or 80.
  • a Cryptic protein:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 50.
  • a Cryptic protein:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 75 and ends at any one of amino acids 116-149 of SEQ ID NO: 75.
  • a Cryptic protein:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 79.
  • Cryptic protein:MISRII heteromultimers are soluble.
  • a Cryptic protein:MISRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic protein:MISRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic protein:MISRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic protein and MISRII homomultimers).
  • a Cryptic protein:MISRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIA polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • a Cryptic family protein 1B:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 9, 10, and 11.
  • a Cryptic family protein 1B:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 9, and ends at any one of amino acids 110-135 of SEQ ID NO: 9.
  • Cryptic family protein 1B:ActRIIA heteromultimers are soluble.
  • a Cryptic family protein 1B:ActRIIA heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:ActRIIA heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:ActRIIA heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and ActRIIA homomultimers).
  • a Cryptic family protein 1B:ActRIIA heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIB polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • a Cryptic family protein 1B:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.
  • a Cryptic family protein 1B:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids 20-29 of SEQ ID NO: 1 and ends at a position corresponding to any one of amino acids 109-134 of SEQ ID NO: 1.
  • a Cryptic family protein 1B:ActRIIB heteromultimer comprises an ActRIIB polypeptide wherein the amino acid position corresponding to L79 of SEQ ID NO: 1 is not an acidic amino acid.
  • Cryptic family protein 1B:ActRIIB heteromultimers are soluble.
  • a Cryptic family protein 1B:ActRIIB heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Cryptic family protein 1B:ActRIIB heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:ActRIIB heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and ActRIIB homomultimers).
  • a Cryptic family protein 1B:ActRIIB heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one TGFBRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • a Cryptic family protein 1B:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 42, 43, 67, or 68.
  • a Cryptic family protein 1B:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-51 of SEQ ID NO: 42 and ends at any one of amino acids 143-166 of SEQ ID NO: 42.
  • a Cryptic family protein 1B:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-44 of SEQ ID NO: 67 and ends at any one of amino acids 168-191 of SEQ ID NO: 67.
  • Cryptic family protein 1B:TGFBRII heteromultimers are soluble.
  • a Cryptic family protein 1B:TGFBRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:TGFBRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:TGFBRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and TGFBRII homomultimers).
  • a Cryptic family protein 1B:TGFBRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one BMPRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • a Cryptic family protein 1B:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 46, 47, 71, or 72.
  • a Cryptic family protein 1B:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 46 and ends at any one of amino acids 123-150 of SEQ ID NO: 46.
  • a Cryptic family protein 1B:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 71 and ends at any one of amino acids 123-150 of SEQ ID NO: 71.
  • Cryptic family protein 1B:BMPRII heteromultimers are soluble.
  • a Cryptic family protein 1B:BMPRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:BMPRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:BMPRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and BMPRII homomultimers).
  • a Cryptic family protein 1B:BMPRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Cryptic family protein 1B polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one MISRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Cryptic family protein 1B:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 533 or 534.
  • the Cryptic family protein 1B:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-30 of SEQ ID NO: 533 and ends at any one of amino acids 82-223 of SEQ ID NO: 533.
  • a Cryptic family protein 1B:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 50, 51, 75, 76, 79, or 80.
  • a Cryptic family protein 1B:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 50.
  • a Cryptic family protein 1B:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 75 and ends at any one of amino acids 116-149 of SEQ ID NO: 75.
  • a Cryptic family protein 1B:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 79.
  • Cryptic family protein 1B:MISRII heteromultimers are soluble.
  • a Cryptic family protein 1B:MISRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Cryptic family protein 1B:MISRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Cryptic family protein 1B:MISRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Cryptic family protein 1B and MISRII homomultimers).
  • a Cryptic family protein 1B:MISRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIA polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • a Crim1:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 9, 10, and 11.
  • a Crim1:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 21-30 of SEQ ID NO: 9, and ends at any one of amino acids 110-135 of SEQ ID NO: 9.
  • Crim1:ActRIIA heteromultimers are soluble.
  • a Crim1:ActRIIA heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:ActRIIA heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:ActRIIA heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and ActRIIA homomultimers).
  • a Crim1:ActRIIA heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIB polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • a Crim1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 1, 2, 3, 4, 5, and 6.
  • a Crim1:ActRIIB heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids 20-29 of SEQ ID NO: 1 and ends at a position corresponding to any one of amino acids 109-134 of SEQ ID NO: 1.
  • a Crim1:ActRIIB heteromultimer comprises an ActRIIB polypeptide wherein the amino acid position corresponding to L79 of SEQ ID NO: 1 is not an acidic amino acid.
  • Crim1:ActRIIB heteromultimers are soluble.
  • a Crim1:ActRIIB heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:ActRIIB heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:ActRIIB heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and ActRIIB homomultimers).
  • a Crim1:ActRIIB heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one TGFBRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • a Crim1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 42, 43, 67, or 68.
  • a Crim1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-51 of SEQ ID NO: 42 and ends at any one of amino acids 143-166 of SEQ ID NO: 42.
  • a Crim1:TGFBRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 23-44 of SEQ ID NO: 67 and ends at any one of amino acids 168-191 of SEQ ID NO: 67.
  • Crim1:TGFBRII heteromultimers are soluble.
  • a Crim1:TGFBRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:TGFBRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:TGFBRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and TGFBRII homomultimers).
  • a Crim1:TGFBRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one BMPRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • a Crim1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 46, 47, 71, or 72.
  • a Crim1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 46 and ends at any one of amino acids 123-150 of SEQ ID NO: 46.
  • a Crim1:BMPRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 27-34 of SEQ ID NO: 71 and ends at any one of amino acids 123-150 of SEQ ID NO: 71.
  • Crim1:BMPRII heteromultimers are soluble.
  • a Crim1:BMPRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ).
  • a Crim1:BMPRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling).
  • Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:BMPRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and BMPRII homomultimers).
  • a Crim1:BMPRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim1 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one MISRII polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 537 or 538.
  • the Crim1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 35-37 of SEQ ID NO: 537 and ends at any one of amino acids 873-939 of SEQ ID NO: 537.
  • a Crim1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 50, 51, 75, 76, 79, or 80.
  • a Crim1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 50.
  • a Crim1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 75 and ends at any one of amino acids 116-149 of SEQ ID NO: 75.
  • a Crim1:MISRII heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 17-24 of SEQ ID NO: 50 and ends at any one of amino acids 116-149 of SEQ ID NO: 79.
  • Crim1:MISRII heteromultimers are soluble.
  • a Crim1:MISRII heteromultimer of the disclosure binds to one or more TGF-beta superfamily ligands (e.g., binds to one or more TGF-beta superfamily ligands with a K D of at least 1 ⁇ 10 ⁇ 7 ). In some embodiments, a Crim1:MISRII heteromultimer of the disclosure inhibits one or more TGF-beta superfamily ligands (e.g., inhibits Smad signaling). Heteromultimer-ligand binding and inhibition may be determined using a variety of assays including, for example, those described herein (e.g., in vitro binding and/or cell-based signaling assays).
  • a Crim1:MISRII heteromultimer of the disclosure has a different TGF-beta ligand binding and/or inhibition profile (specificity) compared to a corresponding homomultimer (e.g., Crim1 and MISRII homomultimers).
  • a Crim1:MISRII heteromultimer of the disclosure is a heterodimer.
  • the disclosure relates to heteromultimers that comprise at least one Crim2 polypeptide, which includes fragments, functional variants, and modified forms thereof, and at least one ActRIIA polypeptide, which includes fragments, functional variants, and modified forms thereof.
  • the Crim2:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NOs: 541, 542, 545, or 546.
  • the Crim2:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 26-138 of SEQ ID NO: 541 and ends at any one of amino acids 1298-1503 of SEQ ID NO: 541.
  • the Crim2:ActRIIA heteromultimer comprises a polypeptide that is at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 95%, 96%, 97%, 98%, 99%, or 100% identical to a polypeptide that begins at any one of amino acids of 24-138 of SEQ ID NO: 545 and ends at any one of amino acids 539-814 of SEQ ID NO: 545.

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